Honing Indications for Endocrine Therapy in ER-Low Early Breast Cancer

 

• More than 40% of Americans with estrogen receptor (ER)-low early breast cancer did not receive endocrine therapy, analysis of a national database showed.
• Omitting endocrine therapy in ER-low breast cancer was associated with a 23% relative increase in the risk of death in 3 years, driven by patients with 6-10% ER expression.
• Patients with residual disease after neoadjuvant chemotherapy also had significantly worse survival without endocrine therapy.

Omission of endocrine therapy in estrogen receptor (ER)-low early breast cancer had a significant association with worse survival, particularly in patients with residual disease after neoadjuvant chemotherapy (NAC), a large retrospective analysis showed.

Among women with ER expression of 1-10%, omitting endocrine therapy was associated with a 23% increased risk of death in 3 years (HR 1.23, 95% CI 1.04-1.46). Patients with ER expression of 6-10% accounted for most of the excess risk. In a subgroup analysis of patients who received NAC, overall survival (OS) was significantly worse in those who had residual disease and did not receive endocrine therapy.

The study provided data relevant to an unresolved controversy in managing early breast cancer, reported Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota, and coauthors in the Journal of Clinical Oncologyopens in a new tab or window.

"We saw that over 40% of oncologists and patients omit endocrine therapy [in ER-low disease]," Goetz told MedPage Today. "I think that points to the controversy. No one really knows quite what to do."

"What we can say from our study is that it looks like not everybody is going to benefit from endocrine therapy," he added. "What we have to do as a community is identify those patients who are most likely to get the benefit from endocrine therapy."

The 10,000+ patients included in the analysis had high-risk early breast cancer; about 70% received NAC and/or adjuvant chemotherapy in accordance with current clinical guidelines.

The study suggested that patients who do not attain a complete response (residual disease) are most likely to benefit from endocrine therapy: in the subgroup of patients who received NAC, omission of endocrine therapy did not significantly affect OS in patients who achieved a pathologic complete response (HR 1.06, 95% CI 0.62-1.80) but was associated with worse OS among patients who had residual disease after NAC (HR 1.26, 95% CI 1.00-1.57, P=0.046).

"The reason is probably pretty simple," said Goetz. "If you have residual disease, you're likely to have enrichment of tumor cells that are ER positive. We didn't look at that but other people have in the past. So one of our recommendations would be to retest the tumor that remains in the breast after chemotherapy. You could have a tumor that starts out 1-10% [ER expression] and you eliminate the ER clones with chemotherapy, and what remains are surviving cancer cells that are estrogen receptor positive, tumor cells that obviously would benefit from endocrine therapy."

Standard of care for early ER-positive breast cancer includes 5-10 years of adjuvant endocrine therapy, which has been shown to reduce recurrence, decrease breast cancer mortality, and improve OS, independent of response to chemotherapy. Omission and decreased adherence to endocrine therapy are associated with worse survival, Goetz and coauthors noted.

ER-low tumors (1-10% expression) have histologic characteristics and response to NAC similar to those of ER-negative breast cancer, which has led guideline authors to classify ER-low breast canceropens in a new tab or window as a separate entity from ER-positive tumors. However, the benefits of endocrine therapy in ER-low breast cancer have remained unproven, the authors continued.

In their present study, an effort to provide information to assist decision making, Goetz and colleagues queried the National Cancer Databaseopens in a new tab or window for patients with high-risk stage I-III, ER-low breast cancer from 2018 to 2020. The search identified 10,362 patients, of whom 7,018 received chemotherapy.

This cohort had a median age of 55 at breast cancer diagnosis and 73% were white. Tumors were largely PR-negative (73%), HER2-negative (65%), grade 3 (74%), and of invasive ductal histology (92%).

Overall, 42% of patients did not receive endocrine therapy. Omission of endocrine therapy was associated with progesterone receptor-negative status, HER2 negativity, higher histologic grade, Ki-67 values ≥20, and NAC. During a median follow-up of 3 years, 586 patients died.

Omission of endocrine therapy did not significantly affect the risk of death among patients with ER expression of 1-5% (HR 1.15, 95% CI 0.91-1.45) but had a significant association with mortality risk in patients with ER expression of 6-10% (HR 1.42, 95% CI 1.00-2.02, P=0.048).

"Further research is needed to identify the biological subtypes of ER-low BCs [breast cancers] that are most likely to benefit from ET [endocrine therapy]," the authors concluded. "Until then, patients with ER-low BC should be counseled regarding the potential benefit of ET."

Disclosures

The study was supported by the National Cancer Institute.

Goetz disclosed relationships with Lilly, AstraZeneca, Blueprint Medicines, Genzyme, ARC Therapeutics, RNA Diagnostics, Seagen, Engage Health Media, Novartis, Sermonix Pharmaceuticals, BioTheryX, Laekna, Tersera, BeiGene, bioTheranostics, Puma Biotechnology, eChinaHealth, Intellisphere, Context Therapeutics, Atossa Therapeutics, Biovica, Eagle Pharmaceuticals, Loxo, Pfizer, and SimBioSys.

Primary Source

Journal of Clinical Oncology

Source Reference: opens in a new tab or windowChoong GM, et al "Endocrine therapy omission in estrogen receptor-low (1%-10%) early-stage breast cancer" J Clin Oncol 2025; DOI: 10.1200/JCO-24.02263.

https://www.medpagetoday.com/hematologyoncology/breastcancer/115154